The development of T cells which are genetically modified to express a chimeric antigen receptor (CAR) has opened the door for many new potential therapies for cancers and other disorders. Generally, CARs comprise an extracellular antigen recognition domain and an intracellular domain. The exact composition of the intracellular domain can provide unique characteristics to the CAR and to the cell population expressing the CAR.
CD278 or Inducible-T-cell costimulator (ICOS) is a costimulatory molecule that is generally expressed on activated T cells. It has been shown that in addition to CD28, signaling via the inducible costimulator (ICOS, also called CD278) is required for optimal cytokine secretion, because both molecules are essential for optimal IL-17A secretion by murine Th17 cells (Park et al., 2005 Nat. Immunol. 6:1133-1141). Recent findings in murine models have revealed that ICOS amplifies Th17 responses by inducing the expression of the transcription factor c-MAF and therefore transactivating IL-21 production (Bauquet et al., 2009 Nat. Immunol. 10:167-175). While chimeric receptors that comprise ICOS have been generated (U.S. Patent Publication US2006/0247191), it is unknown what role the ICOS domain has in influencing CAR mediated anti-tumor activity, CAR mediated Treg proliferation, or T cell persistence.
Depending on the microenvironmental cues present, naïve CD4+ T cells may differentiate into one of several T helper (TH) cell lineages, including TH1, TH2, Th17, TH22, and regulatory T (Treg) cells (O'Shea et al., 2010 Science 327:1098-1102; Murphy et al., 2010 Nat. Immunol. 11:674-680). Th17 cells augment host defense, have a major role in mucosal immunity, enhance a number of autoimmune diseases, and release cytokines, including IL-17A and IL-17F (Korn et al., 2009 Annu. Rev. Immunol. 27:485-517). The contribution of Th17 cells to tumor immunity varies, showing the potential for both antitumorigenic and protumorigenic activity (Zou et al., 2010 Nat. Rev. Immunol. 10:248-256). Therefore, identification of the mechanisms that control Th17 responses is essential to understand tumor immunity. Despite recent advances in CAR-based therapies for treating cancers, there has yet to be any known therapy using genetically redirected Th17 cells.
Thus, there is an urgent need in the art for compositions and methods for treatment of cancer using CARs that increase the anti-tumor activity and persistence of genetically redirected Th17 cells. The present invention addresses this need.